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Equine Research

Q&A with Veterinarian/Researcher James MacLeod

James MacLeod, a veterinarian and researcher at the Maxwell H. Gluck Equine Research Center and director of UK’s Equine Initiative, came to UK from Cornell in 2004. In 2009, principal investigator Jinze Liu (computer science), MacLeod, and Arne Bathke and Arnold Stromberg (statistics) received more than $1 million in federal stimulus funds from the National Science Foundation to develop computer-based methods to study gene expression. I met with MacLeod at the Gluck Center in August to find out just how powerful genomics can be in treating equine and human disease.—Alicia P. Gregory, Editor

Were you interested in horses from the very beginning?

Well, growing up in Delaware I wanted to be a country veterinarian—a horse doctor. I was in the James Herriot generation of veterinary students. [Herriot was an English country veterinarian who wrote “All Creatures Great & Small.”] I did my undergraduate work at the University of Delaware, and as an undergraduate student I was part of an honors program that involved research. I liked it, especially the discovery aspects of research. When I applied to veterinary school the next year, I sent applications to both Cornell University and the University of Pennsylvania. Penn offered me a fellowship funded by the National Institutes of Health that would support my education through a combined veterinary school/Ph.D. degree program. It is called the Medical Scientist Training Program. Most of the leading medical schools have these training grants and Penn has one of the oldest and largest. To my knowledge, it is still the only NIH-funded program in the country that includes positions for veterinary students. Being awarded this fellowship was a fork in the road, directing me towards a career in academia and scientific research.

I still very much identify with being a veterinarian. When people ask me what I do, I say that I am a veterinarian. The common image of a veterinarian is of a clinician in private practice. Veterinarians, however, can also contribute in lots of other arenas—research in academia or private industry, biomedical or agricultural businesses, government regulatory positions, public health, laboratory animal medicine, and conservation biology. I worked for a little bit in clinical practice after veterinary school, but it soon became clear that if I wanted to succeed in science I was going to have to stay focused.

So you don’t miss the clinical side of vet work?

Clinical medicine and patient care are wonderful, but intellectually I struggled with the repetitions of clinical practice. Is your 1,000th dog spay as exciting as the first one you perform? Probably not. Then, there’s the potential that when an interesting case does come along, the owners might not be motivated to pursue the clinical work up or your recommended treatment because of economic considerations, or perhaps the hospital where you work does not have the equipment that you need. It’s funny how life works out, but I think ending up in biomedical research was the best outcome for me and where I am happiest and most productive. I still very much think about clinical problems and patient care, but I try to contribute through discovery science and participate through research collaborations with clinicians in both veterinary and human medicine.

How did you end up at Cornell University?

After finishing veterinary school and a Ph.D., I accepted a position at the University of Pennsylvania medical school where I worked in a laboratory studying the expression of genes that are important in the regulation of fetal growth in children. I stayed in this wonderful children’s hospital for three and a half years, but then accepted a faculty position at Cornell University in 1992. I worked at Cornell for 12 years, before coming to UK to accept an endowed position in the Department of Veterinary Science. [MacLeod holds the John S. and Elizabeth A. Knight Chair at the Gluck Center.]

What kind of research possibilities has the horse genome opened up?

Sequencing the complete equine genome has opened doors for us and allowed the application of new scientific methods to equine biology that we’d certainly thought about before, but never been able to actually use. Genomics enables powerful research technologies, but finding the answers still requires high quality experiments.

I was motivated to embrace genomic strategies in part because I wanted my research to be data-driven. We study joint cartilage and osteoarthritis. I can make educated predictions, based on my experience and the scientific literature, that this gene or that protein might be important for any given biological issue. But all scientists are limited by our lack of knowledge. Through transcriptional profiling and our computational strategies for analyzing data from a new technique called RNA sequencing, we can examine all of the expressed genes. The method allows scientists to assess the “whole forest” (whole genome) before selecting specific “trees” (individual genes) to study at greater detail. Instead of relying on predictions, we can analyze the primary data reflective of the entire genome to determine where the interesting biology is occurring.

Because genomic approaches are data-driven, you often find unexpected relationships. It’s nice when you see the expected ones because that validates your thinking—that you’re asking the right question—but concurrent with the expected ones, you often find some totally unexpected biological events that you would never have thought of.

One major challenge, however, is that transcriptional profiling and other genomic experiments generate huge data files—the kind that can’t be handled by the average desktop computer. That’s motivating all of us to become more computer-savvy and encouraging collaborations with computer scientists. My perception is that computer scientists love biological datasets because they’re tangible and they’re huge. The rapidly growing fields of bioinformatics and computational biology are being driven by intellectual synergies between computer science and biology.

The name of your stimulus-funded project “Exon Splice Pattern Characterization of the Whole mRNA Transcriptome” is a mouthful. Why are you looking at mRNA?

Messenger RNA (mRNA) is a short-lived molecule that transfers genetic information from the nucleotide sequence of DNA to generate a specific sequence of amino acids during protein synthesis. Essentially, the identity and amount of different mRNA transcripts in a cell or tissue reflects the pattern of gene expression. Our computer-based algorithms allow us to capture a “snapshot” of the entire transcriptome—the complete set of RNA molecules—including mRNA that represent all of the genes being actively expressed at that point in time when the sample was collected. This technology informs you about all of the different RNA species that are in the sample and their relative proportions. The assays are expensive—more than $1000, but the level of information generated is so much greater than we had before.

What we are doing was made possible by the technologies developed during the Human Genome Project. These technologies continue to rapidly evolve, but they’re allowing us to sequence whole genomes at speeds that would have been Star Trek-like 5 to 10 years ago. Fortunately, they really work and the cost is coming down. The concept of “personalized medicine”—that our physicians will have our medical history, information from their examination, diagnostic test results, and specific information about our individual genome—isn’t so far away.

How are scientists using RNA transcriptomes?

In addition to the studies on joint cartilage and osteoarthritis in my laboratory, we are collaborating with a group of scientists and physicians in the cancer biology group at UNC Chapel Hill. Different patients can have cancers that appear very much alike when examining the cancer cells under a microscope. But on a molecular level—on the level of differential gene expression—there can be major and important differences. By looking at the gene expression profile of different cancer types, it may be possible to accurately determine the origin of the cancer, identify which drugs or other therapeutic strategies will be most effective in treatment, or perhaps what the patient’s prognosis will be. This is a rapidly evolving field of medicine, but the possibilities are truly exciting. In the near term, we will be analyzing clinical samples with these genomic methods, utilizing algorithms and computational pipelines to analyze gigabytes of primary data, and providing physicians (and veterinarians) with important new information for patient care.

So what does all this have to do with your laboratory’s work on osteoarthritis in horses?

The progression of arthritis involves a breakdown and loss of joint cartilage over time. Essentially, we all suffer from it. Sixty to 80 percent of senior citizens have clinically significant arthritis. High level athletic competition can cause more aggressive wear and tear on joints. Add in corticosteroid injections and pain medications, and athletes can reach the end of their career somewhere in their 20s with the same level of joint disease as people several decades older. Diseases related to strenuous physical activities are very similar in horses and humans. For the musculoskeletal system, horses get essentially all of the same bone problems as human athletes, the same cartilage pathologies, and very similar types of tendon and ligament injuries. As elite athletes, horses can inform us about issues in sports medicine and exercise physiology that have direct relevance to human health.

A general area of interest in my laboratory is related to why some cells can fully repair tissue injuries (like bone cells), while others cells with the same set of genes (like nerve and cartilage cells) cannot. When you fracture a bone, if you reduce the fracture and stabilize it, the bone will normally heal completely. And consider the liver: it’s exposed to toxic substances throughout life, but is very efficient at repairing any damage. If the liver couldn’t do this, we’d probably all die from liver failure. But why can’t nervous tissue repair or regenerate? If you suffer a transecting spinal cord injury—you’re paralyzed. Cartilage is right there with nerve cells, with a very limited intrinsic capacity for repair. That’s why arthritis is a progressive disease. The cartilage cells are unable to repair structural surface lesions and over time the damage usually gets worse. The idea of regenerative medicine is to figure out if we can get these tissues to fully repair and restore normal structure and function. So we are conducting experiments on cartilage cells—normal cartilage, osteoarthritic cartilage, and the repair tissue that forms in joint surface lesions. We are studying gene expression starting with a broad assessment at the level of the whole mRNA transcriptome, looking for unexpected findings that may provide novel and important new knowledge.

Gluck center grad student tackles Wobbler Syndrome

Jennifer Janes, a veterinarian and graduate student the Department of Veterinary Science at the University of Kentucky, received a two-year $100,000 fellowship grant from the Morris Animal Foundation, and received the American Association of Equine Practitioners (AAEP) Foundation Past Presidents’ Research Fellow award. These awards are supporting her research on Wobbler Syndrome (cervical stenotic myelopathy).

Wobbler Syndrome is a devastating neurological disease that pinches the spinal cord and causes a horse to lose coordination. Factors thought to contribute to the development of the disease include genetics, high planes of nutrition, trauma, rapid growth, and decreased copper/increased zinc levels. However, veterinarians do not understand the underlying cause or details of the disease’s progression.

Janes is working with James MacLeod, the John S. and Elizabeth A. Knight Chair, professor of veterinary science at the Gluck Equine Research Center, and director of UK’s Equine Initiative; Stephen Reed, Rood & Riddle Equine Hospital; and Neil Williams, associate director at the UK Veterinary Diagnostic Laboratory (VDL).

Wobbler Syndrome is one of the most common causes of neurologic disease in Thoroughbreds and usually does not resolve with time and rest. Given the poor prognosis for recovery, the disease has a substantial emotional and financial impact on Thoroughbred owners and the horse industry.
Janes will revisit unanswered questions about Wobbler Syndrome by using recent research developments and diagnostic technology. She will also examine the role of abnormal bone and cartilage formation in neck vertebrae, as well as identify regions of DNA and specific genes that are involved in the disease process.

“Results of the study will enhance our understanding of the cause and progression of Wobbler Syndrome, advanced imaging and DNA-based diagnostic technologies, and provide a scientific foundation for research on improved management and therapeutic practices for this serious disease,” Janes says.

A native of Illinois, Janes graduated from the University of Tennessee College of Veterinary Medicine in 2006. She completed a one-year internship at Wisconsin Equine Clinic & Hospital. While there, Janes developed an interest in musculoskeletal diseases. Janes is working simultaneously on a Ph.D. at the Gluck Center with MacLeod and board certification in pathology with Williams at the UKVDL.

—Jenny Blandford, Gluck Equine Research Foundation assistant. This article first appeared in the Bluegrass Equine Digest. For more equine research stories, sign up to receive the Bluegrass Equine Digest monthly free e-newsletter at http://www.thehorse.com/Enewsletter/Register.aspx.

James MacLeod and Jennifer Janes

James MacLeod (left), the John S. and Elizabeth A. Knight chair at the Maxwell H. Gluck Equine Research Center, and graduate student Jennifer Janes are both veterinarians in the Department of Veterinary Science.

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